Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic. The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. We are engaged in genetic studies to identify FSGS risk genes. We have found four genes to date: WT1 (Wims tumor-1), WIT1 (Wilms tumor interacting gene-1), PDSS2 (enzyme in the ubiquinone synthesis pathway) land NPHS2 (podocin). A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus. In order to identify causes of idiopathic collapsing glomerulopathy, we have initiated studies to identify possible viral causes, using blood and urine derived DNA and RNA applied to a viral gene chip. Our progress during the past year included the following: 1) We completed and published our identification, using admixture mapping, of MYH9 (encoding nonmuscle myosin IIA) as a major effect risk factor for FSGS and HIV-associated collapsing glomerulopathy. Current efforts include the following: - identifcation of the risk variant (by genomic sequencing and by sequencing of transcripts from glomeruli and urine-derived podocytes) - extension to other kidney diseases, including lupus nephritis, sickle cell nephropathy, pre-eclampsia, and renal transplantation - characterization of the phenotpye of hypertensive patients with kidney disease and MYH9 risk variants - studies involving MYH9 heterozygous knock-out mice, MYH9 over-expressing mice, and podocyte-specific MYH9 knockout mice 2) tentative identification of cardiotrophin-like cytokine 1 as a component of the FSGS permeability factor, involved in FSGS recurrence following renal transplantation